Insulin has been reported to have effects not only in peripheral tissues, but also in the brain to regulate satiety, glucose homeostasis and energy balance. Insulin receptors (IRs) are widely expressed in the brain, particularly in the arcuate nucleus (Arc) of the hypothalamus, in subsets of anorexigenic pro-opiomelanocortin (POMC), orexigenic agouti-related peptide (AgRP) and neuropeptide Y (NPY)-expressing neurons. However, while global neuronal deletion of IR lead to an obese phenotype, mice lacking IR only in POMC or AgRP neurons exhibit unaltered food intake and energy homeostasis. This indicates that other neurons in the hypothalamus may be responsible for mediating insulin’s action on the regulation of energy metabolism and food intake. The importance of the central NPY system in the regulation of food intake and energy expenditure is well established. Increased NPY levels contribute to the development of obesity in a two-fold manner by increasing food intake as well as reducing energy expenditure and thermogenesis. Although a subset of NPY neurons in the ARC also expresses AgRP, the large majority of hypothalamic NPY neurons are not co-localized with this neurotransmitter. To address the specific role of insulin in NPY neurons, we generated NPY neuron-specific IR deficient mice (NPYCre/+;IRlox/lox). Our preliminary results showed that NPYCre/+;IRlox/lox mice have significantly increased body weight gain as compared to control mice. Importantly, the increase in body weight gain in NPYCre/+;IRlox/lox mice is associated with an increase in fat mass.  Additionally, we observed a strong trend toward increased food intake and reduced energy expenditure in NPYCre/+;IRlox/lox mice, suggesting that the increased body weight and adiposity may be due to energy imbalance. Taken together, these preliminary results suggest that impaired insulin receptor signaling in NPY neurons may be causally linked to the development of obesity.